4-Hydroxy-N-substituted morphinan derivatives

ABSTRACT

Novel 4-hydroxy morphinan derivatives, which may bear a variety of N-substituents, are disclosed. These morphinans are useful as analgesic agents and are also useful as antagonists of certain strong analgesics such as morphine.

United StatES Patent 11 1 Mohacsi et al.

[451 Oct. 21, 1975 4-HYDROXY-N-SUBSTITUTED MORPHINAN DERIVATIVES [75] Inventors: Ernest Mohacsi, Nutley; Willy Leimgruber, Montclair, both of NJ.

[73] Assignee: Hofimann-La Roche Inc., Nutley,

22 Filed: Feb. 26, 1974 21 Appl. No.: 446,084

Related U.S. Application Data [60] Division of Ser. No. 299,478, Oct. 20, 1972, Pat. No. 3,810,899, which is a continuation-in-part of Ser. No. 233,715, March 10, 1972, abandoned.

[52] U.S. Cl. 260/285 [51] Int. Cl. C07D 221/28; A61K 31/485 [58] Field of Search 260/285; 424/260 [56] References Cited UNITED STATES PATENTS 2,524,855 10/1950 Schidner et al 260/285 2,524,856 10/1950 Schidner et al 260/285 2,885,401 5/1959 Griissner et al.... 3,285,922 11/1966 Gates 260/285 FOREIGN PATENTS OR APPLICATIONS 764,632 12/1956 United Kingdom 260/285 Primary Examiner-Paul M. Coughlan, Jr.

Assistant ExaminerDiana G. Rivers Attorney, Agent, or FirmSamuel L. Welt; BernardS. Leon; Frank P. Hoffman [57] ABSTRACT 6 Claims, No Drawings 4-HYDROXY-N-SUBSTITUTED MORPHINAN DERIVATIVES RELATED APPLICATIONS application of Ser. No. 233,715 filed Mar. 10, 1972 and now abandoned.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel 2- and 4- hydroxymorphinans. More particularly, this invention covers 2- and 4-hydroxymorphinan derivatives which may bear a variety of N-substituents. The invention further comprehends processes for making these novel morphinans and novel intermediates employed in these processes.

More specifically, the compounds of the present invention are selected from the group consisting of compounds of the formula wherein R signifies hydroxy, lower alkoxy, or acyloxy and R signifies hydrogen, lower alkyl, cycloalkyl-lower alkyl, aryl-lower alkyl, lower alkenyl or lower alkynyl, the pharmaceutically acceptable acid addition salts thereof and the optical antipodes thereof.

As used herein, the term lower alkyl either alone or in combination refers to straight and branched chain hydrocarbon groups containing from 1 to 7, preferably from 1 to 4, carbon atoms such as, for example, methyl, ethyl, propyl, isopropyl, butyl, t-butyl and the like with methyl being preferred. The term lower alkenyl" in- III cludes straight and branched chain hydrocarbon groups containing from 2-7 carbon atoms, wherein at least one carbon to carbon bond is unsaturated, such as allyl, butenyl, di-methyl allyl and the like.. The term lower alkynyl refers to groups such as propargyl and the like. The term cycloalkyl refers to cyclic hydrocarbon groups containing from 3-7 carbon atoms such as cyclopropyl, cyclobutyl, cyclopentyl. cyclohexyl and the like with cyclopropyl being preferred. The term lower alkoxy refers to both straight and branched chain alkoxy radicals containing from 1 to 7 carbon atoms such as methoxy, ethoxy, propoxy, butoxy and the like, with methoxy being preferred. The term *acyloxy includes both lower alkanoyloxy and aroyloxy groups. The term lower alkanoyloxy" refers to both straight and branched chain aliphatic carboxylic acid moieties containing from 2 to 7 carbon atoms such as acetoxy, propionyloxy, butyryloxy and the like, with acetoxy being preferred. The term aroyloxy" refers to aromatic carboxylic acid moieties such as benzoyloxy and the like. The term aryl" denotes the organic radical derived by the removal of a hydrogen atom from an aromatic hydrocarbon, such as, for example, phenyl or phenyl substituted by halogen, nitro, lower alkyl or lower alkoxy.

The compounds of formulae l and ll above can be prepared following a variety of procedures:

A. In one process aspect of the present invention, the compounds of formula 1 above in which R signifies lower alkoxy and R signifies hydrogen, i.e. compounds of the formula are prepared via a series of steps, the key step involving the acid catalyzed cyclization of a l-(m-alkoxybenzyl)- l,2,3,4,5,6,7,8-octahydroisoquinoline substituted in the 2-position, i.e. on the nitrogen, with an electron withdrawing group followed by the base catalyzed hydrolysis of the electron withdrawing group. A detailed description of this preparative approach to morphinan derivatives is found in the Leimgruber, Mohacsi U.S. Pat. No. 3,634,429 issued Jan. 11, 1972.

In the first step of this process aspect, cyclohexen( l yl-ethylamine (III) is condensed with m-alkoxyphenylacetic acid (IV) to yield N-2-(l-cyclohexen-lyl)ethyl-m-alkoxyphenylacetamide (V). This reaction can be depicted as follows:

lower alkoxy COOH . into lower alkoxy The condensation of the compounds of formulae Ill and IV is preferably effected in the presence of an inert organic solvent such as toluene or xylene and at the reflux temperature of the reaction medium with continuous removal of the water being formed.

The so-obtained compound of formula V is then cyclized. employing a Bischler-Napieralski type cyclization with phosphorus oxychloride to yield a compound of the formula:

lower alkoxy This cyclization to the compound of the formula VI is expediently effected in the presence of an inert organic solvent such as toluene or'xylene at elevated temperatures.

The compound of formula VI is then reduced. for example with sodium borohydride, to yield the corresponding octahydroisoquinoline of the formula CH VII ower alkoxy The electron withdrawing group is then introduced the 2-position of the l-(m-alkoxybenzyl)- octahydroisoquinoline molecule. The electron withdrawing groups drastically reduce the basicity of the nitrogen atom. Representative of such groups suitable for the purposes of the present process are formyl, acetyl, benzoyl and sulfonyl, with formyl being the most preferred. The method of introducing the electron withdrawing group into the compound of formula VI] varies with the nature of the group but is usually achieved following conventional procedures. Thus, for example, a formyl group can be introduced by reacting the formula Vll compound with methyl formate or with chloral; an acetyl group can be attached by acetylation with acetic anhydride in pyridine. The formula Vll compound can be ethoxy carboxylated with ethyl chloroformate, or benzoylated with benzoyl chloride. In a preferred aspect, the compound of formula Vll is formylated with methyl formate in the presence of a catalytic amount of sodium methoxide to yield a compound of the formula VIII lower alkoxy The 1-(m-alkoxybenzyl)-octahydroisoquinoline bearing an electron withdrawing group in the 2- position, as represented by the compound of formula VIII, is then cyclized using acid catalysis to yield a mixture of the 2- and 4-alkoxymorphinans, each of which bears the electron withdrawing group on the nitrogen atom.

The acids which can be employed to catalyze this cyclization are preferably phosphoric acid or polyphosphoric acid (PPA), either singly or in admixture with sulfuric acid. These acids can be used in the presence of solvents but they need not be. The concentration of the acid used is not critical, but for convenience commercially available concentrated acids are used.

The 2-alkoxymorphinan bearing an electron withdrawing group on the nitrogen atom, which is the major reaction product obtained upon cyclization of the 1-malkoxybenzyl)-octahydroisoquinoline having an electron withdrawing group in the 2-position, is then isolated from the mixture by conventional separation techniques, such as column chromatography, countercurrent distribution, liquid-liquid extraction and fractional crystallization, with fractional cyrstallization being the preferred technique. It should be noted that if the l-(m-alkoxybenzyl)-octahydroisoquinoline is resolved into its optically active antipodes prior to cyclization, as will be discussed in detail hereinafter, cyclization yields a mixture of the appropriate antipodes of the 2- and 4-alkoxy morphinans bearing the electron withdrawing group on the nitrogen. Separation of the 2- and 4-substituted antipodes is then expediently effected by first removing the electron withdrawing group to yield the corresponding NH compounds as de-' scribed hereafter. Then the Z-alkoxy antipode is isolated by first preparing a suitable salt, preferably the lower alkoxy NCHO The electron withdrawing group present on the nitrogen can then be removed using conventional techniques. for example, acid or base hydrolysis. When the preferred formyl group is used, base hydrolysis is preferable, employing alkali metal hydroxides such as sodium hydroxide and potassium hydroxide or alkaline earth metal hydroxides such as calcium hydroxide. Removal of the electron withdrawing group yields the 2- alkoxymorphinan of formula Ia above.

The N-formyl intermediate of formula IX above is novel and as such is a part of the present invention.

In another process aspect, the N-formyl compound of formula IX can be reduced, for instance with lithium aluminum hydride, to yield the corresponding 2-alkoxy-Nmethylmorphinan. Alternatively, this N- methyl derivative can be prepared by the reductive methylation of the compound of formula Ia above employing aqueous formaldehyde and hydrogen in the presence of Raney nickel.

It should also be noted that, if desired. the malkoxybenzyloctahydroisoquinoline can be converted to the mhydroxybenzyloctahydroisoquinoline which after formylation followed by cyclization gives a mixture of 2- and 4-hydroxy-N-formylmorphinan.

B. In another process aspect of the present invention. the compounds of formula I wherein R, signifies hydroxy can be prepared by treating the corresponding compound wherein R is lower alkoxy with an ether cleaving reagent. The ether cleavage can be effected using aqueous acids such as hydrobromic acid or hydroiodic acid, Lewis acids such as boron tribromide, or pyridine hydrochloride, with pyridine hydrochloride being preferred.

C. In still another process aspect, the compounds of formula I above wherein R signifies acyloxy can be prepared by the acylation of the corresponding compound wherein R signifies hydroxy. If R in the acylated product is to be other than hydrogen, it is preferalower alkoxy ble to first prepare the desired N-substituted derivative and then to acylate this derivative by using one molar equivalent or a slight excess over this of the acylating agent, in order to avoid unwanted by-products whose formation can beintiatedby acylation of the nitrogen atom, Acylation can be accomplished following conventional techniques; as, for example, by treating the- Z-hydroxy-Nsubstituted-morphinan with an acylating agent such as an acid anhydride. e.g. acetic anhydride, or an acid halide. e.g. acetyl chloride.

D. In a further process aspect of the present invention. the N- substituted morphinans of formula I above are prepared from the corresponding compounds wherein R is hydrogen following conventional techniques. Thus, for example, the N-unsubstituted com pound can be reacted with an alkylating agent to introduce the R substituent.- Suitable alkylating agents for this purpose include alkyl halides such as, methyl iodide, ethyl bromide, cyclopropylmethyl chloride. and the like and alkenyl halides such as allyl bromide. This alkylation reaction is preferably effected in the presence of an inert organicsolvent, such as dimethylformamide.

Alternatively, the N-substituent can be introduced by acylation of the NH compound followed by reduction of the amide to the desired R group. The acylation canbe effected using conventional procedures, employing as the acylating agent acid anhydrides, such as acetic anhydride, isobutyric anhydride, propionic anhydride or acid halides. such as acetyl chloride. nvaleryl chloride, propionyl chloride, cyclopropane carboxylic acid chloride, cyclohexane carbonyl chloride, phenylacetyl chloride and the like. The acylation reaction can be effected in the presence of an inert organic solvent, such as benzene, methylene chloride, and the like and at room temperature or elevated temperatures.

The N-acylated morphinan is then reduced. for example, by treatment with lithium aluminum hydride. diisobutylaluminum hydride or sodium bis(-2- methoxyethoxy)aluminum hydride, to yield the desired N-substituted compound of formula I. Introduction of the N-substituent by this method can be depicted by the following Reaction Scheme A, in which preferred groups are shown.

H l l .ower alkoxy lower alkoxy NCH In the above reaction scheme. R is lower alkyl cy- :loalkyl. cycloalkyl-lower alkyl. aryl. aryl-lower alkyl. ower alkcnyl or lower alkynyl.

If it is desired to prepare N-substituted morphinans vf formula I where R is hydroxy via the acylationeduction technique depicted in Reaction Scheme A, he N-substituent should be introducted first into the I-alkoxymorphinan and the alkoxy group then con- 'erted to the hydroxy group by the ether cleavage pro- :edure discussed in the process aspect B above. if it is lesired to prepare N-substituted-morphinans of fornula l in which R is an acyloxy group by this procelure. the N substituent should be introduced before ac- CH O NCHO

ylation of the 2-hydroxy group.

The intermediates of formula X in Reaction Scheme A are novel and as such form a part of the instant invention.

E. In a further process aspect, the compounds of formula ll are prepared from the mother liquor remaining after the isolation of the 2-alkoxyor 2- hydroxymorphinan as described in process aspect A above. The remaining mother liquor contains a mixture of the 2- and 4-substituted-morphinansv Separation of the 4-substituted compound is shown in the following Reaction Scheme B, in which the preferred groups and reagents are depicted.

REACTION SCHEME B H 1 CH0 (a) NaOH -'(b) 1) CH O 2) Ra-Ni/H CHO ca o

H NLRB As shown in step (a), the mixture of the 2- and 4- substituted morphinans is hydrolyzed, preferably with methanolic sodium hydroxide, to remove the electron withdrawing group, the preferred formyl group being shown here. In step (b), the NH compound is reductively methylated by treatment with formaldehyde followed by Raney-nickel/hydrogen reduction. The N- methylmorphinans are prepared since they form crystalline salts more readily than the N-unsubstituted morphinans; however, it is possible to proceed directly from step (a) to step (c).

In step (c), the N-methylmorphinans'are treated with an acid that will yield a crystalline acid addition salt, preferably salicylic acid. In step (d) the 2- and 4- substituted isomers can be separated in the form of their salts, preferably their salicylates, by conventional separation techniques, with fractional crystallization being preferred.

Preparation of the 4-hydroxymorphinans can be effected following the same procedure as described above in process aspect B for the Z-hydroxy derivatives. Furthermore, the 4-acyloxy compounds can be prepared following the same general procedures as set forth in process aspect C above.

The N-substituted compounds of formula II can be prepared from the --NH compounds by employing the same techniques as outlined in process aspect D above. Alternatively, these compounds can be prepared by reacting the N-methy] derivative with the appropriate acid halide, preferably chloride, and then reducing the resulting amide, for example, with lithiumaluminum hydride, to obtain the desired N-substituted-morphinan of formula ll. Thus, for example, the N-methyl compound can be reacted with cyclopropylcarboxylic acid chloride in toluene and then the amide reduced with LAl-l to obtain the N-cyclopropylmethylmorphinan of formula ll above.

NCH

COOH

TNCH

As is obvious from the structure of the compounds of formulae 1 and ll above, these compounds can exist in racemic form or as their optical antipodes. In the event an optical antipode rather than the racemate is the desired end product, some of the intermediates or the final products can be resolved by means well known in the art, for example, by formation of diastereomeric salts. This can be accomplished by reacting the racemic mixture of either an intermeidate or the end product with an optically active acid. Suitable acid for this purpose include tartaric acid, camphorsulfonic acid, di-(ptoluoyl)-tartaric acid, ()-di-O-isopropylidene-Z-keto- L-gulonic acid [()-DAG] and the like. The reaction between the racemic mixture and the optically active acid is preferably effected in the presence of a lower alkanol such as methanol, ethanol, propanol and the like with ethanol being preferred. The two diastereomer'ic salts thus obtained can then be separated because of their differing physical characteristics, i.e., solubility, crystal formation, etc. This separation is effected following standard techniques, for example. fractional crystallization, distillation, and the like, with fractional crystallization being preferred. After separation, the individual diastereomeric salts can be converted to the free optically active base by treatment with base. Suitable bases for this purpose include alkali metal hydroxides such as sodium hydroxide, potassium hydroxide and the like, alkaline earth metal hydroxides such as calcium hydroxide, and ammonium hydroxide, with ammonium hydroxide being preferred. It is advantageous to resolve the required starting materials, particularly the l-(m-alkoxybenzyl)-1,2,3,4,5,6,7,8- octahydroisoquinolines. at the outset into the dextroor levo-rotatory forms, depending upon the desired absolute configuration of the end product.

The compounds of formula I and ll above form pharmaceutic'ally acceptable acid addition salts with inorganic acids. Thus, the compounds of the present invention form pharmaceutically acceptable acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid; and with organic acids such as tartaric acid, citric acid,

acyloxy alkyl, methyl is preferred; and when R is lower alkenyl, allyl and dimethyl allyl are preferred.

One preferred class of compounds falling within the scope of formulae l and ll above are those wherein R signifies acyloxy, i.e.. compounds of the formula and or the formula camphorsulfonic acid, ethanesulfonic acid, toluenesulfonic acid, salicyclic acid, ascorbic acid, maleic acid,

succinic acid, formic acid, acetic acid and the like.

Preferred among the compounds of formulae I and H and of the formula above are those wherein R signifies hydroxy. In the cases where R denotes lower alkoxy, methoxy is preferred; and when R signifies acyloxy, acetoxy is preferred. When the R substituent is cycloalkyl-lower alkyl, cyclopropylmethyl is preferred; when R is lower acyloxy wherein R is as described above.

Another preferred class of compounds falling within the scope of formulae l and ll above are those wherein R signifies hydroxy, i.e., compounds of the formula wherein R signifies hydrogen, lower alkyl containing from 3 to 7 carbon atoms, cycloalkyl-lower alkyl, lower alkenyl, lower alkynyl, or aryl lower alkyl; and R is as described above.

Also preferred of the compounds within the scope of formulae I and II above are-tho'se' wherein R, signifies methoiiy',*i'le., compounds of lower alkoxy. preferably the formula loweralltoxy and of the formula lower alkoxy wherein R andR are as described above.

The most preferred of the compounds of formulae 1 and Il above are:

(i)-4-methoxy-N-methylmorphinan (i)-2-methoxy-N-cyclopropylmethylmorphinan (+)-2-methoxy-N-cyclopropylmethylmorphin )-2-methoxy-N-cyclopropylmethylmorphinan (+)-4-methoxy-N-cyclopropylmethylmorphinan (-)-4-methoxy-N-cyclopropylmethylmorphinan (+)-2-acetoxy-N-cyclopropylmethylmorphinan ()-2-acetoxy-N-cyclopropylmethlmorphinan (i)-2-hydroxy-N-cyclopropylmethylmorphinan (+)-4-hydroxy-N-cyclopropylmethylmorphinan ()-4-methoxy-N-methylmorphinan I ()-4hydroxy-N-methylmorphinan (+)-2'hydroxy-N-cyclopropylmethylmorphinan (-)-2-hydroxy-N-cyclopropylmethylrnorphi'nan (:)-2hydroxy-N-allylmorphinan (+)-2-hydroxy-N-allylmorphinan ()-2-hydroxy-N-allylmorphinan (:)-2-hydroxy-N-(3,3-dimethylallyl)morphinan (+)-2-hydroxy-N-dimethylallylmorphinan (-)-2-hydroxy-N-dimethylallylmorphinan (-)-4-hydroxy-N-cyclopropylmethylmorphinan (:)-4-hydroxy-N-methylmorphinan.

The compounds of formulae 1 and II above, in racemic form or as the dextro-rotary or levo-rotatory antipods, and the pharmaceutically acceptable acid addition salts of these racemates or optically active antipodes are useful as anagesic agents and are also useful as antagonists of certain strong analgesic agents such as morphine. Their pharmaceutically useful activities are demonstrated in warm-blooded animals using standard procedures.

i The analgesic activit y of the compounds of formulae l and'il above is demonstrated in the standard phenylquinone'writhing test (Sigmund et al., Proc. Soc. Exp.

III I I Biol. 1142.1. 729, 1957. This testis ted to measure the analgesic effects of compounds in mice exposed to intra-abdominally induced chemical pain. Five male: CF I mice, weighing 20-22 gms. were used per dose level. The ED was the dose which reduced the total.

number of writhes by 50%. When the following representative compounds of thee present inventionare uti- 1 lized as the test substances, analgesic activity is observed as shown for the following ED levels:

Representative compounds of formulae I and II above effectively counteract morphine analgesia. This activity can be demonstrated in the mice tail flick test for morphine antagonism. This test is used to measure narcotic antagonism. Compounds are given subcutaneously l0 minutes prior to morphine sulfate. The percent elevation in reaction time was determined during each test for 10 mg/kg s.c. of morphine sulfate and actual percent increase was used in calculating the per-' lized as the test substance, morphine antagonism activ-' ity is observed as shown by the following ED levels:

(i)-2-hydroxy-N-cyclopropylmethylmorphinan ED 8 mg/kg (s.c.) (+)-2-hydroxy-N-cyclopropylmethylmorphinan ED 8 mg/kg (s.c.) (-)-2-hydroxy-N-cyclopropylmethylmorphinan ED 7.5 mg/kg (s.c.)

(i)-2-hydroxy-N-allylmorphinan mg/kg (s.c.)

(-)-2-hydroxy-N-allylmorphinan ED 5 mg/kg (+)-4-hydroxy-N-cyclopropylmethylmorphinan ED 5.2 mg/kg (s.c.) ()-4-hydroxy-N-cyclopropylmethylmorphinan Ed 16.0 mg/kg (s.c.)

The compounds of formulae 1 and 11, their enantiomers and salts as herein described can be incorporated into standard pharmaceutical dosage forms, for example, they are useful for oral or parenteral application with the usual pharmaceutical adjuvant material, for example, organic or inorganic inert carrier materials 11.1611 as water, gelatin, lactose, starch, magnesium steaate, talc,vegetable oils, gums, polyalkyleneglycols and ihe'like. The pharmaceuticalpreparations can be em-' )loyed in a solid form, for example, as tablets, troches, ,uppositories,"capsules, or in liquid form, for example, 18 solutions, suspensions or emulsions. Pharmaceutical ldjuvant materials can be added and include preserva ives, stabilizers, wetting or emulsifying agents, salts to :hange the osmotic pressure or to act as buffersQThe Jharmaceutical preparations can also contain other :herapeutically active substances. The following examples further illustrate the :invenion. All temperatures are in degrees Centigrade unless :pecified otherwise.

EXAMPLE 1 Preparation of N-2-( 1-cyclohexen-l'-yl)ethyl mmethoxyphenylacetamide A mixture of 75.0 g. (0.60 mol.) of cyclohexen( l )-yl- :thylamine and 100.0 g. (0.60 mol) of 3-methoxyvhenylacetic acid in 500 ml. of xylene was heated at relux for 7 hr. with removal of the water by means of a )ean-Stark apparatus. After evaporation of the solent. 200 ml. of hexane was added to the residue and he product was allowed to crystallize at room temperaure. The crude amide was separated by filtration, and ecrystallization from cyclohexane afforded pure N-2- cyclohexen-1-yl)-ethyl-m-methoxyphenylacetamide, 120 ml. of POCl and 500 m1. ofdry toluene was heated at 100 for 0.5 hr. under nitrogen. After evaporation of the solvent and excess reagent, the residue was triturated with petroleum ether (2 X 150 ml.). The petroleum ether insoluble material was dissolved in methylene chloride (600 ml.) and the solution washed successively with dilute aqueous ammonium hydroxide (600 ml.) and water (200 ml.). After drying, the solvent was removed in vacuo to ,give the crude hexahydroi soquinoline which .was dissolved in methanol (500 ml.) and immediately reduced by portionwise addition of 25.0 g. (0.66 mol) of sodium borohydride over 2.5 hours with stirring at 2030. The reaction mixture was stirred at room temperature overnight. The methanol was distilled off and the residue was partitioned between ether (500 ml.) and dilute aqueous ammonium hydroxide. The ethereal solution was washed with water, dried and evaporated to give crude (i)-l-(mmethoxybenzyl)-1 ,2,3,4,5,6,7,8- octahydroisoquinoline, b.p. 160164/O.3 mm.

A solution of (i)-l-(m-methoxybenzyl)- 1,2,3,4,5,6,7,8-octahydroisoquinoline, 196.0 g. (0.76

l-cyclohexen-1-yl)ethyl-m methoxyp henylacetamide;

EXAMPLE 2 (0.22 mol) of N-2-(l- A mixture of 60.0 g.

mol), in ethyl acetate (600 ml.) was saturated with dry hydrogen bromide and the hydrobromide allowed to crystallize at room temperature, the crystals were filtered and dried. The crude product was recrystallized from isopropanol to give pure (i)-l-(mmethoxybenzyl)-1,2,3,4,5 ,6,7,8-octahydroisoquinoline hydrobromide, m.p. l8ll83.

A solution of 3.8 g. (0.015 mol) of (i)-1-(mmethoxybenzyl)-1,2,'3,4,5 ,6,7,8-octahydroisoquinoline in 10 ml. of-acetone was treated with a solution of 3.0

g. of oxalic acid in ml. of acetone. The crystals were EXAMPLE 3 v v I Preparation of (i)-1-(m-rnethoxybenzyl)-N -formyl-l,2,3,4,5,6,7,8- octahydroisoquinoline (i)-l-(m-MethoxybenzyU-l,2,3,4,5,6,7,8- octahydroisoquinoline hydrobromide, 200.0 g. (0.59 mol), was suspended in dilute aqueous sodium hydroxide and the suspensions was extracted several times with methylene chloride (1 1.). The combined methylene chloride extracts were dried and the solvent was removed in vacuo to give the crude (i)-l-(mmethoxybenzyl)-N-formyl-1,2,3,4,5,6,7,8- octahydroisoquinoline. It was dissolved in a mixture of 325 ml. of methyl formate and 1.04 g. of sodium methoxide and the solution heated at refluxovernight. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in ether (500 ml.) and washed successively with 1N hydrochloric acid (400 ml.) and water ml.). The ethereal solution was dried and evaporated to give 'crude (:t)-l-(mm'ethoxybenzyl)-N-formy1-l,2,3,4,5,6,7,8- octahydroisoquinoline. A sample of this compound was distilled, b.p. l87190/0.2 mm. and crystallized. m.p. 7143". i a

' v EXAMPLB 4 Preparation of (i)-2- and (i)-4-methoxy-N-formylmorphinan (i)-l-(m-Methoxybenzyl)-Nformyl-1,2,3,4,5 ,6,7,8-

bined under stirring with 1125 g. of phosphoric acid which had been mixed with 22.5 g. of conc. sulfuric acid and the mixture was heated in a nitrogen atmosphere to 70. The resulting homogeneous solution was kept at 70 for 38 hours. The reaction mixture was cooled in an ice bath and 41. of ice-water was added. The resulting suspension was extracted several times with ethyl acetate (a total of 4 l. the combined organic phases were washed with water and dried. Filtration and concentration gave crude (i)-2- and (:)-4- methoxy-N-formylmorphinan, b.p. 1952l0/0.l mm.

EXAMPLE 5 Separation of (i)-2-methoxy-N-formylmorphinani The cyclization product, 1 10.0 g. (0.38 mol), consist- I EXAMPLE 6 Preparation of (i)-2-methoxymorphinan (i)-2-Methoxy-N-formylmorphinan, 38.7 g. (0.13 mol), was dissolved in 900 ml. of methanol and 350 ml. of 2.5N aqueous sodium hydroxide was added. After heating at reflux for 41 hours, the methanol was removed under reduced pressure and the resulting aqueous suspension was extracted with ether (3 X 330 ml.). The combined ethereal extracts were washed with water and dried. Removal of the solvent in vacuo yielded crude (i)-2-methoxymorphinan, b.p. 130-140/0.07 mm.

(t)-2 Methoxymorphinan, 1.0 g. (0.004 mol), on treatment with hydrogen chloride (anhydrous) in 3 ml.

of ethy l acetate afforded the crude hydrochloride, which after recrystallization from acetone gave pure (i)'2-methoxymorphinan hydrochloride.

EXAMPLE 7 Preparation of (i)-2-methoxy-N-methylmorphinan To a suspension of 1.5 g. of lithium aluminum hydride in 200ml. of anhydrous tetrahydrofuran, 20.0 g. (0.07 mol) of (i- )-2-methoxy-N-formylmorphinan in 100 ml. of anhydrous tetrahydrofuran was added dropwise. After the mixture had been refluxed for 3 hours under nitrogen, it was cooled to room temperature and ethyl acetate followed by water were added dropwise. The resulting suspension was dried, filtered and the filtrate concentrated in vacuo to give crude (id-2- methoxy-Nmethylmorphinan. A sample of this compound was distilled, b.p. 185205/0.025 mm., then crystallized from petroleum ether. m.p. 77.

EXAMPLE 8 Preparation of (i)-2-methoxy-N-methylmorphinan (i)-2-Methoxymorphinan, 10.8 g. (0.042 mol), was dissolved in 250 ml. of methanol and added to 9 ml. of aqueous formaldehyde (37%). The solution was allowed to stand at room temperature overnight. After addition of 8.0 g. of Raney nickel and 250 ml. of methanol, the mixture was hydrogenated at room temperature for 20'hours. The catalyst was removed by filtration and washed with methanol. The solvent was evaporated in vacuo giving crude (i)-2-methoxy-N- methylmorphinan. The above base in 75 ml. of ethyl acetate was treated with a saturated solution of hydrogen chloride and kept at 0 for 1 hour. The product was separated by filtration to give the crude hydrochloride, m.p. 246 (dec.). Recrystallization from acetonitrile gave pure (i)-2-methoxy-N-methylmorphinan hydrochloride, m.p. 255256.

v EXAMPLE 9 Preparation of (i)-2-hydroxy-N-methylmorphinan A. (i)-2-methoxy-N-methylmorphinan, 4.0 g. (0.014 mol) in 50 ml. of 48% l-lBr was refluxed for 15 hours. The cooled solution was made basic with cone. ammonium hydroxide. The precipitate was filtered, and recrystallized from benzene-hexane to give (i)-2- hydroxy-N-methylmorphinan, m.p. 9193.

B. A mixture of 10.0 g. (0.036 mol) of (i)-2- methoxyN-methylmorphinan and g. of pyridine hydrochloride was heated at 220 with stirring under nitrogen for 25 minutes, cooled in an ice bath, and diluted with 100 ml. of water. The mixture was made basic with cone. ammonium hydroxide and extracted with chloroform (900'ml.). The chloroform layer was washed with water and dried. Removal of the solvent EXAMPLE 10 Preparation of (i')-2-acetoxy-N-methylmorphinan A mixture of 4.74 g. (0.018 mol) of (i)-2-hydroxy- N-methylmorphinan and 20 g. of acetic anhydride was heated at reflux for 3 hours. The excess reagent was removed in vacuo and the residue partitioned between 300 ml. of ether and 100 ml. of 2N potassium hydroxide. The ether layer was washed with 50 ml. of water,

dried and concentrated to give crude (i)-2-acetoxy-N- methylmorphinan, 157168/0.75 mm.

(i)-2 -acetoxy-N-methylmorphin'an, 4.8 g. (0.016 mol) in 30 ml. of acetone, on treatment with a solution of 1 .5g. of oxalic acic in30 ml. of acetone, gave (i)-2- acetoxy-N-methylmorphinan oxalate hydrate, m.p.

969 8. A sample of this compound was recrystallized from acetone, m.p. ll03.

EXAMPLE 11 Preparation of (i)--2-hydroxymorphinan A mixture of 2.0 g. (7.7 mmol) of (:t)-2 methoxymorphinan and 20 g. of pyridine hydrochloride was heated at 220 with stirring under nitrogen for minutes, cooled in an ice bath and diluted with 50 ml. of water. The mixture was'made basic with conc. ammonium hydroxide and extracted with chloroform (400 ml.). The extract was washed with '20 ml. of'water and dried. Removal of the solvent gave the crude phenol, m.p. 265 (dec.). Recrystallization from methanol gave pure (1-)-2-hydroxymorphinan, mLp. 275 (dec.).

- EXAMPLE l2 Preparation of (i)-2-hydroxy-Nallylmorphinan A mixture of 6.5 g. (0.027 mol) of (:)-2- hydroxymorphinan, 3.9 g. of allylbromide. 4.6 g. of sodium bicarbonate and 65 ml. of dimethylformamide was stirred and refluxed under nitrogen for 4 hours. The reaction mixture was filtered and the filter cake washed with ethanol. The solvent was removed in vacuo and the product was dissolved in 200 ml. of ether and filtered from a small amount of insoluble material. The ether solution was extracted with 30 ml. of hydrochloric acid in 120 ml. of water. Addition of conc. am-' monium hydroxide to the aqueous phase precipitatedthe crude product which was separated by filtration. This was dissolved in chloroform and dried. Removal of the solvent in vacuo gave '(i)-2-hydroxy-N- allylmorphinan, which when recrystallized from acetonitrile. had a melting point of l'72l74.' (i)-2- Hydroxy-N-allylmorphinan, 7.2 g. (0.025 mol), on treatment with hydrogen chloride (anhydrous) in ethyl acetate afforded (i)-2-hydroxy-N-allylmorphinan hydrochloride, m.p. 270-27l.

EXAMPLE 13 Preparation of (i)-2-hydroxy-N-( 3 ,3-dimethylallyl )morphinan A mixture of 500 mg (2.0 mmol) of (i)-2- hydroxymorphinan, 370 mg. of anhydrous powdered potassium carbonate, 330 mg. of dimethylallyl bromide. and 7 ml. of dimethylformamide was heated at 120 with stirring under nitrogen for 5 minutes. The reaction mixture was cooled and poured into 10 ml. of water. The aqueous mixture was extracted into 100 ml. of ethyl acetate and the ethyl acetate layer was washed with water. After drying the solvent wasremoved in vacuo to give the crude product. Recrystallization from ethanol-water (4:1) gave pure (i)-2-hydroxy- N-(3,3-"

dimethylallyl)morphinan, m.p. 175l77.

A sample of163 mg. (0.53 mmol.) of (i)-2'-hydroxy- N-(3,3-dimethylallyl) morphinan, on treatment with a saturated solution of hydrogen bromide in ethyl acetate afforded (i)-2-hydroxy-N-(3,3-dimethylallyl)morphi- I nan hydrobromide which, after crystallization from water, melted at 234236(dec.).

A sample of 21.35 g. (0.067 mol) of (i)-2-hydroxy- N-(3,3-dimethylallyl) morphinan on treatment with a 20 saturated solution of hydrogen chloride (anhydrouslin ethyl acetate afforded crude hydrochloride. Recrystalliz'ation from ethanol-hexane gave (ji)-2-hydroxy-N- (3,3-dimeth'ylallyl)morphinan hydrochloride, m. p. 2 3 8 240 (dec.).

EXAMPLE 15 Preparation of (ij-Z-niethoxy-N-valerylmorphinan To 10.0 g. (0.039 mol) of (:)-2-methoxymorphinan,' 9.4 g. ofn-valeryl chloride was added dropwise at over 25 minutes-The reaction'mixture was stirred at this temperature for an additional 13 minutes and after" cooling to room temperature, was partitioned between 400 ml. of chloroform and 200 ml. of dilute ammonium hydroxide. The chloroform layer was washed with 100 ml. of water and dried. Removal of the solvent gave crude (i)-2-methoxy-N-valerylmorphinan, which on distillation had a"b.p. of-2l5-235/0.15 mm.

EXAMPLE l6 Preparation of (i)-2-methoxy-N-cyclopropylcarbonylmorphinan To a mixture of g. (0.058 mol) of 2 methoxymorphinan, 40 ml. oftriethylamine and' 150 ml. of methylene chloride was added dropwise over a period of 45 minutes, a solution of l0 g; of cyclopr opane carboxylic acid chloride in 5.0 ml. ofmethylene chloride.,After the mixture had been refluxed for 15 hours, it was cooled to room temperature and washed successively with water, 2N hydrochloric acid, saturated sodium carbonate-solution and water. After drying, the solvent was removed in vacuo to give crude (i)-2-methoxy-N-cyclopropylcarbonylmorphinan,

which on distillation had a b.p. of 190210/0.05 mm.

v EXAMPLE 17 Preparation of (i)-2 rnethoxy-N-isobutyroylmorphina n A mixture of -10.0 g (0.039. mol) of -2-,

methoxymorphinan and 1 2.3. g. of isobutyric anhydride washeated at .100 for 25 minutes. The reaction mixture was evaporated to dryness and the residue partitioned, between ZOO ml. ofether and 50ml. of diluted ammoniumhydride. The. ether layer was washed with 25ml. of water and dried. Removal of the solvent gave crude (35 )-2methoxy-N-isobutyroylmorphinan, which on distillation had a b.p. of 180-l86/0.l mm.

EXAMPLE 18 Preparation of (:)-2methoxy-N-cyclohexylcarbonylmorphinan To a solution of 10.1 g. (0.039 mol) of (i)-2- methoxymorphinan in 40 ml. of benzene was added dropwise at room temperature over 5 minutes 11.5 g. of cyclohexane carbonyl chloride. The reaction mix ture was refluxed for 2 hours, then cooled to room temperature. The solvent was removed in vacuo. The residue was partitioned between 250 ml. of chloroform and 150 ml. of dilute ammonium hydroxide. The chloroform layer was washed with 50 ml. of water and dried. Removal of the solvent gave crude (i)-2methoXy-N- cyclohexylcarbonylmorphinan, which on distillation had a b.p. of 222-250/0.l5 mrn.

EXAMPLE 19 Preparation of (i)-2-methoxy-N-phenylacetylmorphinan To a solution of 10.5 g. (0.041 mol) of (i)-2- methoxymorphinan in 40 ml. of benzene was added dropwise at room temperature for 5 minutes, 12.1 g. of phenylacetyl chloride. After refluxing for 2 hours, the reaction mixture was cooled to room temperature and the solvent removed in vacuo. The residue was partitioned between 300 ml. of methylene chloride and 150 ml. of diluted ammonium hydroxide. The methylene chloride layer was washed with 50 ml. of water and dried. Removal of the solvent gave crude (i)-2- methoxy-N-phenylacetylmorphinan, which on distillation had a b.p. of 235260/O.l mm.

EXAMPLE 20 Preparation of (i)-2-methoxy-N-ethyllmorphinan To a suspension of 1.33 g. of lithium aluminum hydride in 50 ml. of anhydrous ether, was added dropwise a solution of 10.5 g. (0.035 mol) of (:)-2-methoxy-N- acetylmorphinan in 90 m1. of anhydrous ether. After the mixture has been refluxed for 8 hours, under nitrogen it was cooled to room temperature and 80 ml. of ethyl acetate followed by 35 ml. of water were added dropwise. The resulting suspension was dried and filtered, and the filtrate concentrated in vacuo to give crude (i)-2-methoxy-N-ethylmorphinan, which on distillation had a b.p. of 175-210/0.35 mm.

(1:)-2-Methoxy-N-ethylmorphinan, 2.5 g. (0.0088 mol), on treatment with hydrogen chloride (anhydrous) in ethyl acetate, afforded the crude hydrochloride, which after crystallization from 200 ml. of acetone gave (:)-2-methoxy-N-ethylmorphinan hydrochloride, m.p. 270274.

EXAMPLE 21 Preparation of (i)-2-methoxy-N-pentylmorphinan To a suspension of 0.65 g. of lithium aluminum hydride in 45 ml. of anhydrous tetrahydrofuran, was added over minutes a solution of 5.8 g. (0.017 mol) of (i)-2methoxy-N-valerylmorphinan in 45 ml. of anhydrous tetrahydrofuran. After the mixture had'been refluxed for 3 hours under nitrogen. it was cooled to room temperature and 50 ml. of ethyl acetate followed by 35 ml. of water were added dropwise. The resulting suspension was dried and filtered, and the filtrate concentrated in vacuo to give crude (i)-2-methoxy-N pentylmorphinan, which on distillation had a b.p. of 210-225/0.l2 mm.

(i)-2Methoxy-N-pentylmorphinan, 1.9 g. (0.058 mol), on treatment with hydrogen bromide (anhydrous) in ethyl acetate afforded the crude hydrobromide. Recrystallization from acetoneether (2:1) gave pure (i)-2-methoxyN-pentylmorphinan hydrobormide, m.p. 237238.

EXAMPLE 22 Preparation of (i)-Z-methoxy-N-isobutylmorphinan To a suspension of 1.1 g. of lithium aluminum hydride in ml. of anhydrous tetrahydrofuran, was added dropwise over 15 minutes a solution of 9.4 g. (0.028 mol) of '(i)-2-methoxy-N- isobutyroylmorphinan in 80 ml. of anhydrous tetrahydrofuran. After the mixture had been refluxed for 2.7

hours under nitrogen it was cooled to room temperature and 65 ml. of ethyl acetate followed by 36 ml. of water were added dropwise. The resulting suspension was dried, filtered and concentrated in vacuo to give crude (i)-2-methoxy-N-isobutylmorphinan, which on distillation had a b.p. of l74210/0.l5 mm.

(i)-2-Methoxy-N-isobutylmorphinan, 2.3 g. (0.0073 mol), on treatment with hydrogen chloride (anhydrous) in ethyl acetate, afforded the crude hydrochloride. Crystallization from acetone-ether (5:1) gave pure (i)-2-methoxy-N-isobutylmorphinan hydrochlo ride, m.p. l75l77.

EXAMPLE 23 Preparation of (i)-2-methoxy-N-cyclopropylmethylmorphinan To a suspension of 2.3 g. of lithium aluminum hydride in 200 ml. of anhyrous tetrahydrofuran was added dropwise over a period of 2 hours, a solution of 19.9 g. (0.058 mol) of (i)-2-methoxy-N- cyclopropylcarbonylmorphinan in 100 ml. of anhydrous tetrahydrofuran. After the mixture had been refluxed under nitrogen for 7 hours, it was cooled to room temperature and ethyl acetate followed by water was added dropwise. The resulting suspension was dried, filtered and the filtrate was concentrated to give crude (i)-2-methoxy-N-cyclopropylmethylmorphinan, which on distillation had a b.p. of l-200/0.075

mm. A

(i)-2-MethoxyN-cylcopropylmethylmorphinan, 12.6 g. (0.04 mol), on treatment with hydrogen bromide (anhydrous) in ethyl acetate, afforded the crude hydrobromide. Recrystallation from isopropanol gave pure (i)-2-methoxy-N-cyclopropylmethylmorphinan hydrobromide, m.p. 248 (dec.).

EXAMPLE 24 To a suspension of 1.6 g. of lithium aluminum hydride in 100 ml. of anhydrous tetrahydrofuran was added dropwise l 1.4 g. (0.031 mol) of (i)-2-methoxy- N-cyclohexylcarbonylmorphinan in 100 ml. of anhydrous tetrahydrofuran. After the mixture had been refluxed for 3 hours under nitrogen, it was cooled to room temperature and 50 ml. of ethyl acetate followed by 40 ml. of water was added dropwise. The resulting suspension was dried and filtered. The filtrate was concentrated in vacuo to give crude (i)-2-methoxy-N- cyclohexylmethylmorphinan, which on distillation had a b.p. of 200-220/0.15 mm.

(i)-2-Methoxy-N-cyclohexylmethylmorphinan, 2.0 g. (0.057 mol), on treatment with hydrogen bromide (anhydrous) in ethyl acetate, afforded the crude hydrobromide. Recrystallization from acetone-ether (1:1) gave pure (i)-2-methoxy-N-cylcohexylmethylmorphinan hydrobromide, m.p. 186188.

EXAMPLE Preparation of (i)-2-methoxy-N-phenethylmorphinan phinan, which on distillation had a b.p. of 220240/0.05 mm.

(i)-2-Methoxy-N-phenethylmorphinan, 2.0 g.

(0.0055 mol), on treatment with hydrogen bromide (anhydrous) in ethyl acetate, afforded the crude hydrobromide. Recrystallization from acetoneether (2:1) gave pure (i)-2-methoxy-N-phenethylmorphinan hydrobromide, m.p. 206208.

EXAMPLE 26 Preparation of (i)-2-hydroxy-N-ethylmorphinan A mixture of 7.0 g. (0.0245 mol) of (i)-2-methoxy-N-ethylmorphinan and 56.0 g. of pyridine hydrochloride was heated at 220 with stirring under nitrogen for 25 minutes, cooled in an ice bath, and diluted with water. The mixture was made alkaline with conc. ammonium hydroxide and extracted with chloroform (3 X 175 ml.). The extracts were washed with 50 ml. of water and dried. Removal of the solvent gave crude (i)-2-hydroxy-N-ethylmorphinan, which on distillation had a b.p. of 200220/0.2 mm; m.p. 7880.

(i)-2-Hydroxy-N-ethylmorphinan, 6.4 g. (0.023 mol), on treatment with hydrogen bromide (anhydrous) in ethyl acetate, afforded the crude hydrobromide. Crystallization from 225 ml. of isopropanol gave pure (:t)-2-hydroxy-N-ethylmorphinan hydrobromid EXAMPLE 27 Preparation of (i)-2-hydroxy-N-pentylmorphinan A mixture of3.5 g. (0.011 mol) of (i')-2-methoxy-N- pentylmorphinan and 28.0 g. of pyridine hydrochloride was heated at 220 with stirring under nitrogen for 25 minutes, cooled in an ice bath and diluted with water. The mixture was made alkaline with cone. ammonium hydroxide and extracted with 400 ml. of chloroform. The chloroform layer was washed with 50 ml. of water and dried. Removal of the solvent gave crude (i)-2- hydroxy-N-pentylmorphinan, which on distillation had a b.p. of 2l0/0.12 mm.

(i")-2-Hydroxy-N-pentylmorphinan, 3.2 g. (0.01 mol), on treatment with hydrogen chloride (anhydrous) in ethyl acetate, afforded the crude hydrochloride. Crystallization from isopro panolether 1:1.5 gave pure (i)-2-hydroxy-N-pentylmorphinan hydrochloride, m.p. 250-25l.

EXAMPLE 28 Preparation of (:t)-2-hydroxy-N-isobutylmorphinan (i)-2-Hydroxy-N-isobutylmorphinan, 4.6 g. (0.015'

mol), on treatment with hydrogen bromide (anhydrous) in ethyl acetate afforded the crude hydrobromide. Crystalllization from acetone gave pure (i)-2- hyddroxy-N-isobutylmorphinan hydrobromide hydrate, m.p. 167l70.

EXAMPLE 29 Preparation of (1')-2-hydroxy-N-cyclopropylmethylmorphinan A mixture of5.5 g. (0.017 mol) of (i)-2-methoxy-N- cyclopropylmethylmorphinan and 18.0 g. of pyridine hydrochloride was heated at 216 with stirring under nitrogen for 16 minutes, cooled in an ice bath and diluted with 60 ml. of water. The mixture was made alkaline with cone. ammonium hydroxide and extracted with chloroform (210 ml.). The chloroform layer was washed with water and dried. Removal of the solvent gave the crude product which was crystallized from ethyl acetate to give (i)-2-hydroxy-N-cyclopropylmethylmorphinan, m.p. 18 8190.

(i)-2-Hydroxy-N-cyclopropylmethylmorphinan, 3.8 g. (0.012 mol), on treatment with hydrogen chloride (anhydrous) in ethyl acetate, afforded the crude hydrochloride, which after crystallization from isopropanolethyl acetate, gave (i)-2-hydroxy-N-cyclopropylmet-' nylmorphinan hydrochloride, m.p. 255257.

EXAMPLE 30 Preparation of (i)-2-hydroxy-N-cyclohexylmethylmorphinan A mixture of 7.3 g. (0.021 mol) of (:)-2-methoxy-N- cyclohexylmethylmorphinan and 62 g. of pyridine hy- 'drochloride was heated'at 220 with stirring under nihydroxy-N-cyclohexylmethylmorphinan, which on distillation had a b.p. of 220-245/0.1S mm.

(i')-2-Hydroxy-N-cyclohexylmethylmorphinan, 6.8

g. (0.02 mol.), on treatment with hydrogen bromide (anhydrous) in 75 ml. of ethyl acetate-methanol (3:1),

afforded the crude hydrobromide. Recrystallization from methanol gave pure (i)-2-hydroxy-N- cyclohexylmethylmorphinan hydrobromide, m.p. 216-217.

EXAMPLE 31 Preparation of (i)-2-hydroxy-N-phenethylmorphinan A mixture of 6.25 g. (0.017 mol) of (i)-2-met hoxy- N-phenethylmorphinan and 55 g. of pyridine hydrochloride was heated at 220 with stirring under nitrogen for 25 minutes, cooled in an ice bath and diluted with water. The mixture was made alkaline with diluted ammonium hydroxide and extracted with chloroform (600 ml.). The extract was washed with 50 ml. of water and dried. Removal of the solvent gave crude (i-)-2- hydroxy-N-phenethylmorphinan, which after crystallization from ether had a m.p. of 192l93.

(i)'2-Hydroxy-N-phenethylmorphinan, 1 1.4 g. (0.033 mol) on treatment with hydrogen bromide (anhydrous) in 200 ml. of ethyl acetate, afforded the crude hydrobromide. Recrystallization from 250 ml. of methanol gave pure (i)-2-hydroxy-Nphenethylmorphinan hydrobromide, m.p. 320 (dec.).

EXAMPLE 32 Preparation of (i)-2-methoxymorphinan D-tartrate The combined mother liquors obtained in the preparation of ()-2methoxymorphinan 1-tartrate as in Example 34 were concentrated to dryness. The residue in 300 ml. of water was decomposed with cone. ammonium hydroxide. The resulting. suspension was extracted with ethyl acetate (3 X 200 ml.) and the combined extracts were dried and evaporated to give the crude (t)-base.

d-Tartaric acid, 37.0 g. (0.24 mol), was dissolved in 170 ml. of hot methanol and combined with a hot solution of 60.7 g. (0.23 mole) of the crude (:)-base'in 80 ml. of methanol. The solution was heated on a steambath for a few minutes, seeded with (:)-base salt and allowed to come to room temperature while stirring over a period of 5 hours. The crystals were then collected by filtration, washed with methanol and dried, thus affording the crude (i)-amine salt, m.p. l90l95,[ct],, +23.1 (c 1.00, H O). Recrystallization from methanaol (600 ml.) gave pure (+)-2- methoxymorphinan d-tartrate, m.p. 201203, [01],, +24.3 (c 1.01, H O).

EXAMPLE 33 Preparation of (+)-2-methoxymorphinan sample of this compound was distilled, b.p. 150158/0.1 mm, [01],} +20.26 (c 0.997, MeOH).

EXAMPLE 34 Resolution of (+)-2-m ethoxymorphinan l-Tartaric acid, 76.0 g. (0.51 mol), was dissolved in 520 ml. of hot methanol and added to a hot solution of g. (0.51 mole) of (i-)-2-methoxymorphinan in -ml. of methanol. The solution was heated on a steambath for a few minutes, seeded with the salt of the base and allowed to come to room temperature with stirring over a period of 16 hours. The crystals were then collected by filtration, washed with methanol and dried thus affording the crude ()-amine salt, m.p. 180-183, [01],, l4.5 (c 0.96 H O). After three recrystallizations from methanol pure (-)-2- methoxymorphinan l-tartrate was obtained. m.p.' 200202, [a],, 24.6 (c 0.99.11 0).

EXAMPLE 35 Preparation of ()-2-methoxymorphinan ()-2-Methoxymorphinan l-tartrate, 37.3 g. (0.09 mol), in 100 ml. of water was decomposed by addition of cone. ammonium hydroxide. The resulting suspension was extracted with ethyl acetate (3 X 350 ml.) and the combined extracts were dried. Removal of the solvent gave ()-2-methoxymorphinan. [01],, 23.8 (c 1.05, MeOH A sample of this compound was distilled, b.p. 158-161/0.1 mm, {Q1 -22.02 (c 0.98, MeOH).

EXAMPLE 36 Preparation of ()-2methoxy-N-methylmorphinan To 12.4 g (0.048 mol) of ()-2-methoxymorphinan in 500 ml. of methanol was added 14 ml. of aqueous formaldehyde (37%). The reaction solution was allowed to stand at room temperature overnight. After the addition of 15 g. of Raney nickel and 500 ml. of ethanol, the mixture was hydroenated at atmospheric pressure at room temperature for 24 hours. The catalyst was removed by filtration, washed with methanol and the solvent evaporated in vacuo to give ()-2- methoxy-N-methylm orphinan, which on distillation had a b.p. of l80/0.5 mm, [cz],, 38.28 (c 0.992, MeOH).

()-2-Methoxy-N-methylmorphinan, 12.4 g. (0.046 mol), on treatment with hydrogen bromide (anhydrous) in ethyl acetate, gave the crude hydrobromide. Recrstyallization from-acetone afforded pure ()-2- methoxy-N-methylmorphinan hydrobromide, m.p. 194l96, [0th, 20.2 (c 1.19, MeOH).

EXAMPLE 37 Preparation of ()-2-hydroxy-N-methylmorphinana A mixture of 12.8 g. (0.047 mol) of ()-2-methoxy- N-methylmorphinan and 100 g. of pyridine hydrochloride was heated at 220 with stirring under nitrogen for 25 min., then cooled in an ice bath and diluted with 100 ml. of water. The mixture was made alkaline with cone.

ammonium hydroxide and extracted with chloroform (3 X 300 ml.). The extracts were washed with water and dried. Removal of the solvent gave crude ()-2- hydroxy-N-methylmorphinan, which after crystallization from ethyl acetate had a m.p. of l80-182, [01],, --40.69 (c 1.15 MeOH). I

()-2-Hydroxy-Nmethylmorphinan, 11.7 g. (0.045 mol), on treatment with hydrogen chloride (anhydrous) in ethyl acetate, afforded the crude hydrochloride, which after recrystallization from isopropanol gave pure ()-2-hydroxyN-methylmorphinan hydrochloride hydrate, m.p. 176l77 (dec.), [r.\ 24.l (c 0.989, MeOH).

EXAMPLE 38 Preparation of ()-2-hydroxymorphinan A mixture of 11.7 g. (0.044 mol) of (-)-2- methoxymorphinan and 100 g. of pyridine hydrochlo ride was heated at 220 with stirring with nitrogen for 25 minutes, then cooled in an ice bath and diluted with 100ml. of water. The mixture was made basic with conc. ammonium hydroxide and extracted with chloroform (880 ml.). The extract was washed with 150 ml. of water and dried. Removal of the solvent afforded the crude phenol. Recrystallization from acetonitrile gave pure ()-2-hydroxymorphinan, m.p. 2092l 1, [01],, 27.89 (c 1.05, MeOH).

EXAMPLE 39 Preparation of ()-2-hydroxy-N-allylmorphinan A mixture of 5.4 g. (0.022 mol) of ()-2- hydroxymorphinan, 3.2 g. of allylbromide, 3.8 g. of sodium bicarbonate and 55 ml. of dimethylformamide was stirred and refluxed under nitrogen for 4 hours. The reaction mixture was filtered and the filter cake washed with ethanol. The filtrate was evaporated in vacuo and the residue was dissolved in 100 ml. of ether and filtered from a small amount of insoluble material.

The ether solution was extracted with 30 ml. of conc.

hydrochloric acid in 120 ml. of water. Addition of conc. ammonium hydroxide to the aqueous phase gave a precipitate of which was removed by filtration. This was dissolved in methylene chloride and dried. Removal of the solvent in vacuo gave ()-2-hydroxy-N- allylmorphinan, which after recrystallization from benzene-hexane had a m.p. of 154-156, [a],, 61.86 (c 1.041, MeOH).

()2-Hydroxy-N-allylmorphinan, 3.1 g. (0.011 mol). on treatment with hydrogen chloride (anhydrous) in ethyl acetate, afforded the crude hydrochloride, which after crystallization from ethanol gave pure ()-2-hydroxy-Nallylmorphinan hydrochloride hemiethanolate, m.p. 224226, [01],, -40.1 (c 1.06, MeOH).

EXAMPLE 40 Preparation of ()-2-hydroxy-Ndimethylallylmorphinan A mixture of 3.7 g. (0.015 mol) of ()-2- hydroxymorphinan, 1.9 g. of sodium bicarbonate, 2.4 g. of dimethylallyl bromide and 48 ml. of dimethylformamide was heated at reflux with stirring under nitrogen for 4.5 hours. The reaction mixture was filtered and the filter cake washed with ethanol. The filtrate was evaporated in vacuo and the residue was dissolved in ether and filtered from a small amount of insoluble material. The ether solution was extracted with 25 ml.

of 2.5N hydrochloric acid. Addition of conc. ammonium hydroxide to the aqueous phase gave a precipitate which was removed by filtration to give ()-2-hydroxy- N-dimethylallylmorphinan, which on distillation had a b.p. of 205210/0.05 mm., [011 7l.1 (c 0.501. MeOH).

()-2-Hydroxy-Ndimethylallylmorphinan, 4.4 g. (0.014 mol). on treatment with hydrogen chloride (anhydrous) in ethyl acetate, afforded the crude hydrochloride, which after crystallization from isopropanol gave ()-2hydroxy-N-dimethylallylmorphinan hydrochloride, m.p. 233-236, [c11 50.3 (c 0.615, MeOH).

EXAMPLE 41 Preparation of ()2-methoxy-Ncyclopropylcarbonylmorphinan To a solution of 23.0 g. (0.09 mol) of ()-2- methoxymorphinan, 7.0 ml. of pyridine and ml. of methylene chloride was added 14.0 g. of cyclopropane carboxylic acid chloride in 50 ml. of methylene chloride dropwise over a period of 45 minutes. After the mixture had been refluxed for 15 hours, it was cooled to room temperature and washed successively with water, 2N hydrochloric acid, saturated sodium carbonate solution and water. After drying, the solvent was removed in vacuo to give ()-2-methoxy-N- cyclopropylcarbonylmorphinan. which on distillation had a b.p. of 200205/0.8 mm, [04],, 128 (c 0.74, MeOH).

EXAMPLE 42 Preparation of ()-2-methoxy-N-cyclopropylmethylmorphinan To a suspension of 3.7 g. of lithium aluminum hydride in 350 ml. of anhydrous tetrahydrofuran was added dropwise over a period of 30 minutes, 27.0 g. (0.083 mol) of ()-2-methoxy-Ncyclopropylcarbonylmorphinan in 150 ml. of anhydrous tetrahydrofuran. After the mixture had been refluxed under nitrogen for 1.5 hours, it was cooled to room temperature, and ethyl acetate followed by water were added dropwise. The resulting suspension was dried, filtered and the filtrate was concentrated to give crude ()-2-methoxyN- cyclopropylmethylmorphinan, which on distillation had a b.p. of -170/0.1 mm, [M 54.6 (c, 2.46, MeOH).

EXAMPLE 43 Preparation of ()-2-hydroxy-N-cyclopropylmethylmorphinan ()2Methoxy-N-cyclopropylmethylmorphinan, 24.0 g. (0.077 mol) was divided into three equal portions, each portion was heated at 220 with 50 g. of pyridine hydrochloride with stirring under nitrogen for 25 minutes, cooled in an ice bath and diluted with 50 ml. of water. Then the aqueous suspensions from the three runs were combined, made alkaline with conc. ammonium hydroxide and extracted with chloroform (1000 ml.). The chloroform layer was washed with water and dried. Removal of the solvent gave crude ()-2- hydroxy-N-cyclopropylmethylmorphinan, which after crystallization from ether had a m.p. of 8591, [01],, 6 2.76 (c 1.04, MeOH).

()-2-Hydroxy-Ncyclopropylmethylmorphinan, 19.6 g. (0.066 mol), on treatment with hydrogen chloride (anhydrous) in ethyl acetate, afforded the crude hydrochloride. Two recrystallizations from isopropanol gave pure ()-2-hydroxy-Ncyclopropylmethylmorphinan hydrochloride, m.p. 262264 (dec [01],, 46.7 (c 1.17, MeOH).

EXAMPLE 44 Preparation of ()2-acetoxyNcyclopropylmethylmorphinan A mixture of 2.19 g. (0.007 mol) of ()-2-hydroxy- N-cyclopropylmethylmorphinan and 20 ml. of acetic anhydride was heated at reflux for 4 hours. The excess reagent was removed in vacuo and the residue was partitioned between ether and dilute ammonium hydroxide. The ether phase was washed with water, dried and concentrated to give crude ()-2-acetoxy-N- cyclopropylmethylmorphinan, which on distillation had a b.p. of 190215/0.3 mm, [a],, 61.41 (c 0.882, MeOH).

()-2-Acetoxy-N-cyclopropylmethylmorphinan, 2.3 g. (0.007 mol), in ether was treated with a solution of 0.7 g. of oxalic acid in ether to give the crude oxalate. Recrystallization from acetone-ethyl acetate afforded pure ()2-acetoxy-Ncyclopropylmethylmorphinan oxalate acetonate, m.p. 100104, [04],, 42.57 (c 0.869, MeOH).

EXAMPLE 45 Preparation of (+)2-methoxy-N-methylmorphinan To a solution of 12.1 g. (0.047 mol) of (+)-2- methoxymorphinan in 500 ml. of methanol was added 14 ml. of aqueous formaldehyde (37%). The reaction solution was allowed to stand at room temperature overnight. After addition of 15.0 g. of Raney nickel and 500 ml. of methanol, the mixture was stirred under hydrogen at atmospheric pressure at room temperature for 24 hours. The catalyst was removed by filtration, washed with methanol and the solvent evaporated in vacuo to give (+)-2-methoxy-N-methylmorphinan, which on distillation had a b.p. of 160165/0.1 mm, [01],, 37.93 (c 1.02, MeOl-l).

(+)-2-Methoxy-N-methylmorphinan, 11.0 g. (0.04 mol), on treatment with hydrogen bromide (anhydrous) in ether, afforded the crude hydrobromide which. after recrystallization from acetone, gave pure (+)2-methoxy-N-methylmorphinan hydrobromide, m.p. 192194, [a],, +20.59 (c 1.00, MeOH).

EXAMPLE 46 Preparation of (+)-2-hydroxy-Nmethylmorphinan A mixture of 11.9 g. (0.044 mol) of (+)-2methoxy-N-methylmorphinan and 100 g. of pyridine hydrochloride was heated at 220 with stirring under nitrogen for 25 minutes then cooled in an ice bath, and diluted with 100 ml. of water. The mixture was made alkaline with conc. ammonium hydroxide and extracted with chloroform (900 ml.). The extract was washed with water anddried. Removal of the solvent gave crude (+)-2-hydroxyN-methylmorphinan, which after crystallization from ether, had a m.p. of 18l-l83, [01],, 25 +41.4 (c 0.45, MeOH).

(+)2Hydroxy-N-methylmorphinan, 11.0 g. (0.04 mol), on treatment with hydrogen chloride (anhydrous) in ethyl acetate, afforded the crude hydrochloride, which after crystallization from ethanol, gave pure (+)-2-hydroxy-N-methylmorphinan hydrochloride hydrate, m.p. 175178, [11],, +24.0 (c 1.39, MeOH).

EXAMPLE 47 Preparation of (+)-2-hydroxymorphinan A mixture of 11.7 g. (0.045 mol) of (+)-2- methoxymorphinan and 100 g. of pyridine hydrochloride was heated at 220 with stirring under nitrogen for 25 minutes, cooled to room temperature and diluted with 100 ml. of water. The mixture was made basic with conc. ammonium hydroxide and extracted with chloroform (800 ml.). The extract was washed with 150 ml. of water and dried. Removal of the solvent afforded the crude phenol. Crystallization from acetonitrile gave pure (+)-2-hydroxymorphinan, m.p. 209-21 1, [01],, +26.41 (c 1.07, MeOH).

.EXAMPLE 48 Preparation of (+)-2-hydroxy-Na1lylmorphinan A mixture of 6.7 g. (0.027 mol) of (+)-2- hydroxymorphinan, 4.0 g. of allylbromide, 4.8 g. of sodium bicarbonate and ml. of dimethylformamide was stirred and refluxed under nitrogen for 4 hours. The reaction mixture was filtered and the filter cake washed with ethanol. The solvent was removed in vacuo and the residue was dissolved in ml. of ether and filtered from a small amount of insoluble material.

The ether solution was extracted with 30 ml. of conc.

hydrochloric acid in ml. of water. Addition of conc. ammonium hydroxide to the aqueous phase gave a precipitate which was removed by filtration. This was dissolved in methylene chloride and dried. Removal of the solvent gave (+)-2-hydroxy-Nallylmorphinan, which after recrystallization from benzene-hexane had a m.p. of l55157, [01],, +63.l3 (c 1.06 MeOH).

(+)-2-HydroxyN-allylmorphinan, 5.5 g. (0.019 mol) on treatment with hydrogen chloride (anhydrous) in ethyl acetate, afforded the crude hydrochloride which after crystallization from ethanol gave pure (+)2-hydroxy-N-allylmorphinan hydrochloride hemiethanolate, m.p. 224-226, [al +40.9 (c 1.20, MeOH).

EXAMPLE 49 Preparation of (+)-2-hydroxy-Ndimethylallylmorphinan A mixture of 1.00 g. (0.004 mol) of (+)-2- hydroxymorphinan, 0.505 g. of sodium bicarbonate, 0.640 g. of dimethylallyl bromide and 12 ml. of dimethylformamide were heated at reflux with stirring under nitrogen for 4.5 hours. The reaction mixture was filtered and the filter cake washed with ethanol. The solvent was removed in vacuo and the residue was dissolved in etherand filtered from a small amount of etherinsoluble material. The ether solution was extracted with 25 ml. of 2.5N hydrochloric acid. Addition of conc. ammonium hydroxide to the aqueous phase gave a precipitate which was removed by filtration to give crude (+)-2-hydroxy-Ndimethylallylmorphinan, m.p. 9395. A sample of this compound was distilled, b.p. 200205/0.2 mm, [(11 +7l.64 (c 1.105, MeOH).

(+)-2Hydroxy-N-dimethylallylmorphinan, 5.1 g. (0.016 mol), on treatment with hydrogen chloride (an hydrous) in ethyl acetate, afforded the crude hydrochloride which after crystallization from acetone, gave pure (+)'2-hydroxy-N-dimethylallylmorphinan hydrochloride, m.p. 230 232", 0.1 +49.7s (c 1.94, MeOH).

EXAMPLE 50 Preparation of (+)-2-methoxy-N-cyclopropylcarbonylmorphinan To a solution of 19.8 g. (0.077 mol) of (+)-2- methoxymorphinan in 140 ml. of methylene chloride and 6.05 g. of triethylamine was added dropwise over a period of 45 minutes, 12.1 g. cyclopropane carboxylic acid chloride in 40 ml. of methylene chloride. After the mixture had been refluxed for 18 hours under nitrogen, it was cooled to room temperature and washed successively with 100 ml. of water, 100 ml. of 2N hydrochloric acid, 100 ml. of saturated sodium carbonate solution and 100 ml. of water. After drying, the solvent was removed in vacuo to give crude (+)-2-methoxy-N- cyclopropylcarbonylmorphinan, which on distillation had a b.p. of2l5-220/0.25 mm, [11],, +152 (c 1.34 MeOH).

EXAMPLE 51 Preparation of (+)-2-methoxy-N-cyclopropylmethylmorphinan To a suspension of 3.3 g. of lithium aluminum hydride in 300 ml. of anhydrous tetrahydrofuran was added dropwise over a period of minutes, 23.6 g. (0.07 mol) of (+)-2-methoxy-N-cyclopropylcarbonylmorphinan in 130 ml. of anhydrous tetrahydrofuran. After the mixture had been refluxed for 1.5 hours under nitrogen, it was cooled to room temperature and 100 ml. of ethyl acetate followed by 25 ml. of water were added dropwise. The resulting suspension was dried, filtered and the filtrate was concentrated to give crude (+)-2-methoxy-N-cyclopropylmethylmorphinan, which on distillation had a b.p. of l85195/0.3 mm, [04],, +59.5 (c 0.85, MeOH).

EXAMPLE 52 Preparation of (+)-2hydroxy-N-cyclopropylmethylmorphinan (+)-2-Methoxy-N-cyclopropylmethylmorphinan, 20.6 g. (0.065 mol) was divided into three equal portions, each portion was heated with 50 g. of pyridine hydrochloride at 220 with stirring under nitrogen for 25 minutes, cooled in an ice bath and diluted with 50 ml. of water. The aqueous suspensions (from the three portions) were combined, made basic with cone. ammonium hydroxide and extracted with chloroform (1500 ml.0 and dried. Removal of the solvent gave crude (+)-2 hydroxy-N-cyclopropylmethylmorphinan, which after crystallization from ether, had a m.p. of 8490, [01],, +63.6 (c 0.705, MeOH).

(+)-2-Hydroxy-N-cyclopropylmethylmorphinan, 18.0 g. (0.06 mol), on treatment with hydrdogen chloride (anhydrous) in ethyl acetae, afforded the crude hydrochloride which. after crystallization from isopropanol, gave pure (+)-2-hydroxy-N-cyclopropylmethylmorphinan hydrochloride, m.p. 262264, [01],, +47.9 (c 0.94. MeOH).

EXAMPLE 53 Preparation of (+)-2-acetoxy-N-cyclopropylmethylmorphinan A mixture of 2.9 g. (0.0097 mol) of (+)-'2-hydroxy- N-cyclopropylmethylmorphinan and 20 ml. of acetic anhydride was heated at reflux for 3 hours. The excess reagent was removed in vacuo and the residue was partitioned between ethyl acetate and aqueous sodium carbonate. The ethyl acetate phase was washed with 50 ml. of 2N NaOH, ml. of water, dried and concentrated to give crude (+)-2-acetoxy-N-cyclopropylmethylmorphinan, which on distillation had a b.p. of l90/0.2 mm, [01],, +59.21 (c 0.86 MeOH) (+)-2-Acetoxy-N-cyclopropylmethylmorphinan, 1.7 g. (0.005 mol), in ether was treated with a solution of 0.6 g. of oxalic acid in ether to give the crude oxalate, which on crystallization from acetone-ether, afforded pure (+)-2-acetoxy-N-cyclopropylmethylmorphinan oxalate acetonate, m.p. 100104, [(11 +41.87 (c 1.06, MeOH).

EXAMPLE 54 Preparation of *-)-2- and (i)-4-methoxymorphinan A crude mixture of (1:1) of 131 g. (0.46 mol) of (i)-2- and (i)-4-methoxy-N-formylmorphinan dissolved in 3 I. of ethanol (2B) and 1.21. of2.5N aqueous sodium hydroxide was heated at reflux for 15 hours, then the ethanol was removed in vacuo and the resulting aqueous suspension extracted with methylene chloride. Removal of the solvent in vacuo yielded a residue. This was dissolved in ethyl acetate and extracted with 2N hydrochloric acid. The aqueous solution was made basic with aqueous sodium hydroxide and extracted with ethyl acetate. The extract was washed with water and dried. Removal of the solvent gave crude (i)-2- and (:)-4-methoxymorphinan.

EXAMPLE 55 Preparation of (:.L)-2- and (i)-4-methoxy-N-methylmorphinan A crude mixture of 75.7 g. (0.29 mol) of (i)-2- and (i)-4-methoxymorphinan in 800 ml. of methanol and 86 ml. of aqueous formaldehyde (37%) was allowed to stand at room temperature for 15 hours. After addition of 85.0 g. of Raney nickel and 2.2 l. of methanol, the mixture was hydrogenated at atmospheric pressure at room temperature for 20 hours. The catalyst was removed by filtration and washed with methanol. The solvent evaporated in vacuo to give crude (i)-2- and 4-methoxy-N-methylmorphinan.

EXAMPLE 56 Preparation of (i)-2-methoxy-N-methylmorphinan salicylate A mixture of (1:1) of 74.3 g. (0.27 mol) of (i)-2- and (i)-4-methoxy-N-methylmorphinan and 42.0 g. of salicyclic acid in 200 ml. of ethyl acetate was heated until solution occurred, then was seeded with (:)-2- methoxy-N-methylmorphinan salicylate and allowed to crystallize. The crystals were then collected by filtration, washed with ethyl acetate and dried, thus affording crude (i)-2-methoxy-N-methylmorphinan salicylate, which after recrystallization from ethyl acetate has a m.p. of 187189.

EXAMPLE 57 Preparation of (t)2-methoxy-N-methylmorphinan (i)-2-Methoxy-N-rnethylmorphinan salicylate, 47.5 g. (0.12 mol), in water was decomposed with cone. am

- monium hydroxide. The resulting suspension was extracted with ethyl acetate and the combined extracts were dried. Removal of the solvent in vacuo gave (i)- 2methoxyNmethylmorphinan.

EXAMPLE 58 Preparation of (:t)-4-methoxy-N-methylmorphinan salicylate The mother liquor obtained in the preparation of (I)2-methoxy-Nmethylmorphinan salicylate was con centrated to a volume of about 75 ml. then seeded with (i)-4-methoxy-Nmethylmorphinan salicylate and allowed to crystallize. The crystals were then collected by filtration, washed with ethyl acetate and dried, thus affording crude (i)-4methoxy-N-methylmorphinan salicylate, which after recrystallization from ethyl acetate has a m.p. of 154-l55.

EXAMPLE 59 Preparation of (i)4-methoxy-N-methylmorphinan (i)-4-Methoxy-Nmethylmorphinansalicylate, 1.5 g. (0.0037 mol), in 20 ml. of water was decomposed by addition of cone. ammonium hydroxide. The resulting suspension was extracted with ether (3 X 25 ml.) and the combined extracts were washed with water and dried. Removal of the solvent gave the crude product, which was distilled, b.p. 175-180/0.1 mm, then recrystallized from ether, m.p. 8081, to give pure (1')- 4-methoxyN-methylmorphinan.

(i)4-Methoxy-N-methylmorphinan, 1.2 g. (0.0044 mol), on treatment with hydrogen chloride (anhydrous) in ethyl acetate, afforded the crude hydrochloride. Recrystallization from isopropanol gave pure (1)- 4-methoxy-N-methylmorphinan hydrochloride, m.p. 240-241.

EXAMPLE 60 Preparation of (:t)-4-hydr0xy-N-methylmorphinan A mixture of 5.0 g. (0.02 mol) of (i)-4-methoxy-N- methylmorphinan and 42 g. of pyridine hydrochloride was heated at 220 with stirring under nitrogen for 25 minutes, then cooled in an ice bath and diluted with 50 ml. of water. The mixture was partitioned between 300 ml. of dilute ammonium hydroxide and 450 ml. of ether. The ether layer was dried and removal of the solvent gave crude (i)4-hydroxy-Nmethylmorphinan, which after recrystallization from ethyl acetate had a m.p. of 218-220.

(i)-4-HydroxyN-methylmorphinan, 3.0 g. (0.012 mol), on treatment with hydrogen bromide (anhydrous) in ethyl acetate, afforded the crude hydrobromide which after recrystallization from isopropanol gave pure (i)'4-hydroxy-N-methylmorphinan hydrobromide, m.p. 265 (dec.).

EXAMPLE 61 Resolution of (i)-4methoxy-N-methylmorphinan A mixture of 15.1 g. (0.056 mol) of (:1-4-methoxy- N-methylmorphinan, 22.0 g. (0.05 mol) of di-(p-toluoyl)l-tartaric acid and 400 ml. of ethanol was heated until solution occurred, then allowed to stand at room temperature for hours. The crystals were then collected by filtration, washed with ethanol and dried, thus affording the crude ()-amine salt, which after two recrystallizations from methanol, gave pure (-)-4-methoxy-N-methylmorphinan di-(p' toluoyl)-1-tartrate, m.p. l67l68, [01],, +832 (c 0.515, MeOH).

EXAMPLE 62 Preparation of ()-4methoxy-Nmethylmorphinan ()-4-Methoxy-Nmethylmorphinan di-(p-toluoyl)- l-tartrate, 29.4 g. (0.047 mol), in water was decomposed with conc. ammonium hydroxide. The resulting suspension was extracted with ether and the combined extracts were dried. Removal of the solvent gave ()-4- methoxy-N-methylmorphinan, [a],, l5.8 (c 1.00. MeOl-l), which after crystallization from hexane. had a m.p. of 98-l00, [01],, l7.24 (c 0.997, MeOH).

()-4Methoxy-N-methylmorphinan, 4.6 g. (0.017 mol), on treatment with hydrogen chloride (anhydrous) in ethyl acetate, afforded the crude hydrochloride, which after recrystallization from ethyl acetate, gave pure ()-4-methoxy-Nmethylmorphinan hydrochloride, m.p. 203205, [111 8.97 (c 0.958, H 0).

EXAMPLE 63 Preparation of (+)-4-methoxy-N-methylmorphinan di( toluoyl )-d-tartrate The combined mother liquors obtained in the preparation of (-)-4-methoxy-N-methylmorphinan di-(ptoluoyl)1-tartrate were concentrated to dryness. The residue in water was decomposed with cone. ammonium hydroxide. The resulting suspension was extracted with ether and the combined extracts were dried. Removal of the solvent gave crude (+)-4-methoxy-Nmetheylmorphinan. The crude (+)-4-methoxy-N-methylmorphinan, 9.2 g. (0.034

mol), 13.0 g. (0.034 mol) of di-(p-toluoyl)-d-tartaric acid and 150 ml. of ethanol was heated until solution occurred, then was allowed to stand at room temperature for 15 hours. The crystals were then collected by filtration, washed with ethanol and dried, thus affording the crude (+)-amine salt. Recrystallization from ethanol gave pure (+)-4-methoxy-N-methylmorphinan di-(-toluoy1)-d-tartrate, m.p. l67-168, [a] ,,80.78 (c 0.519,'MeOH).

EXAMPLE 64 Preparation of (+)-4-methoxy-Nmethylmorphinan EXAMPLE Preparation of ()-4-N-methylmorphinan A mixture of 1.8 g. (0.0066 mol) of ()-4-methoxy- N-methylmorphinan and 20.0 g. of pyridine hydrochloride was heated at 220 with stirring under nitrogen for 25 minutes then cooled in an ice bath and diluted with 20 ml. of water. The mixture was made basic with cone. ammonium hydroxide and extracted with chloroform (100 ml.). The extract was washed with water and dried. Removal of the solvent gave crude ()-4- hydroxy-N-methylmorphinan, which after recrystallization from ether, had a m.p. of 2l6-2l7, [011 34.99 (c 1.07, MeOH).

()-4-Hydroxxy-N-methylmorphinan, 1.70 g. (0.0063 mol), on treatment with hydrogen chloride (anhydrous in 15 ml. of ethyl acetate afforded the crude hydrochloride, which after recrystallization from ethanol, gave ()-4-hydroxy-N-methylmorphinan hydrochloride, m.p. 303305, [111 17.94 (c 0.958, MeOH).

EXAMPLE 66 Preparation of (-)-4-methoxy-N-cyclopropylcarbonylmorphinan To a solution of 11.2 g. (0.041 mol) of ()-4- methoxy-N-methylmorphinan in 95 ml. of dry toluene, 21.6 g. of cyclopropane carboxylic acid chloride in 35 ml. of dry toluene was added dropwise at 5 for 1 hour. The mixture was allowed to warm to room temperature and was then refluxed for hours. The solvent was removed in vacuo and the residue partitioned between ether and 3N hydrochloric acid. The ether layer was washed successively with water, dilute ammonium hydroxide and water and dried. Removal of the solvent afforded the crude product. Recrystallization from ether gave pure ()-4-methoxy-N-cyclopropylcar bonylmorphinan, m.p. 126128, [a] 176.31 (c 1.071, MeOH).

EXAMPLE 67 Preparation of (-)-4-methoxy-N-cyclopropylmethylmorphinan To a suspension of 1.0 g. of lithium aluminum hydride in 85 ml. of anhydrous tetrahydrofuran was added dropwise 7.2 g. (0.022 mol) of )-4-methoxy- N-cyclopropylcarbonylmorphinan in 35 ml. of anhydrous tetrahydrofuran. After the mixture had been refluxed under nitrogen for 3 hours, it was cooled to room temperature and ethyl acetate followed by water was added dropwise. The resulting suspension was dried, filtered and the filtrate was concentrated to give crude ()-4-methoxy-N-cyclopropylmethylmorphinan, which after recrystallization from ethyl acetate had a m.p. of 8284, [011 54.97 (c 1.00, MeOH).

()-4-Methoxy-N-cyclopropylmethylmorphinan, 0.3 g. (0.001 mol), on treatment with hydrogen chloride (anhydrous) in ethyl acetate, afforded the crude hydrochloride, which after two recrystallizations from isopropanol, gave pure ()-4-methoxy-N-cyclopropylmethylmorphinan hydrochloride, m.p. 270-272, [01] -35.29 (c 1.00, MeOH).

EXAMPLE 68 Preparation of ()-4-hydroxyN-cyclopropylmethylmorphinan A mixture of 6.0 g. (0.02 mole) of ()-4-methoxy-N- cyclopropylmethylmorphinan and 50 g. of pyridine hydrochloride was heated at 220 with stirring under nitrogen for 25 minutes, cooled in an ice bath and diluted with 50 ml. of water. The mixture was made basic with cone. ammonium hydroxide and extracted with chloroform (500 ml.). The extract was washed with water and dried. Removal of the solvent gave crude ()-4- hydroxy-Ncyclopropylmethylmorphinan, which after recrystallization from ether had a m.p. of l69l7l, [a] -70.03 (c 1.01, MeOH).

()-4-Hydroxy-N-cyclopropylmethylmorphinan. 3.4 g. (0.011 mol), on treatment with hydrogen chloride (anhydrous) in ethyl acetate, afforded the crude hydrochloride, which after recrystallization from isopropanol, had a m.p. of 271273, [M -51.57 (c 0.99, MeOH).

EXAMPLE 69 Preparation of (+)-4-hydroxy-N-methylmorphinan A mixture of 1.79 g. (0.0066 mol) of (+)-4-methoxy-N-methylmorphinan and 20.0 g. of pyridine hydrochloride was heated at 220 with stirring under nitrogen for 25 minutes, cooled in an ice bath and diluted with 20 ml. of water. The mixture was made basic with cone. ammonium hydroxide and extracted with chloroform. The extract was washed with 20 ml.

of water and dried. Removal of the solvent gave crude (+)-4-hydroxy-N-methylmorphinan, which after recrystallization from ether gave pure (+)-4-hydroxy-N- methylmorphinan, m.p. 2182l9, [M +-33.86, (c 1.01, MeOH).

(+)-4Hydroxy-N-methylmorphinan, 1.39 g. (0.0054 mol), on treatment with hydrogen chloride (anhydrous) in 15 ml. of ethyl acetate, afforded the crude hydrochloride, which after recrystallization from ethanol, gave pure (+)-4-hydroxy-N-methylmorphinan hydrochloride, m.p. 300302, [0:] +l8.08 (c 1.01, MeOH).

EXAMPLE 70 Preparation of (+)-4-methoxy-N-cyclopropylcarbonylmorphinan To a solution of 11.1 g. (0.041 mol) of (+)-4-methoxy-N-methylmorphinan in 95 ml. of dry toluene, 21.6 g. of cyclopropane carboxylic acid chloride in 35 ml. of dry toluene was added dropwise at 5 for 1 hour. The mixture was allowed to warm to room temperature and was then refluxed for 15 hours. The solvent was removed in vacuo and the residue parti tioned between ether and 3N hydrochloric acid. The

ether layer was washed successively with water, dilute,

ammonium hydroxide and water and dried. Removal of the solvent afforded crude (+)-4-methoxy-N- cyclopropylcarbonylmorphinan, which after recrystallization from ether gave pure (+)-4-methoxy-ncyclopropylcarbonylmorphinan, m.p. 126128, [11] +177.06 (c 1.01, MeOH).

EXAMPLE 71 Preparation of (+)-4methoxy-N-cyclopropylmethylmorphinan To a suspension of 1.01 g. of lithium aluminum hydride in ml. of anhydrous tetrahydrofuran was added dropwise, 7.2 g. (0.022 mol) of (+)-4-methoxy- N-cyclopropylcarbonylmorphinan in 35 ml. of anhydrous tetrahydrofuran. After the mixture had been refluxed under nitrogen for 3 hours it was cooled to room temperature and ethyl acetate followed by water was added dropwise. The resulting suspension was dried, filtered and the filtrate was concentrated to give crude (+)-4-methoxy-N-cyclopropylmethylmorphinan,

- which after recrystallization from ethyl acetate, had a m.p. of 8284, [111 +55.94 (c 0.99, MeOH).

(+)-4-Methoxy-N-cyclopropylmethylmorphinan, 0.3 g. (0.001 mol), on treatment with hydrogen chloride (anhydrous) in ethyl acetate, afforded the crude hydrochloride, which after two recrystallizations from isopropanol, gave pure (+)-4-methoxy-N-cyclopropylmethylmorphinan hydrochloride, m.p. 270272, [041 +37.75 (c 1.00, MeOH).

EXAMPLE 72 Preparation of (+)-4-hydroxy-N-cyclopropylmethylmorphinan A mixture of5.8 g. (0.019 mol) of (-l-)-4methoxyl l cyclopropylmethylmorphinan and 50 g. of pyridine hydrochloride was heated at 220 with stirring under nitrogen for 25 minutes, cooled in an ice bath and diluted with 50 ml. of water. The mixture was made basic with conc. ammonium hydroxide and extracted with chloroform (500 ml.). The extract was washed with water and dried. Removal of the solvent gave crude (+)-4- hydroxy-N-cyclopropylmethylmorphinan, which after recrystallization from ether had a m.p. of l6917l, [04] +68.7 (c 0.73, MeOH).

(+)-4-Hydroxy-N-cyclopropylmethylmorphinan, 5.0 g. (0.02 mol), on treatment with hydrogen chloride (anhydrous) in ethyl acetate, afforded the crude hydrochloride, which after recrystallization from isopropanol gave pure (+)-4-hydroxy-Ncyclopropylmethylmorphinan hydrochloride, m.p. 271273, [a] +51.91 (c 1.04, MeOH).

EXAMPLE 73 Resolution of (i)-1-(m-methoxybenzyl)-l ,2,3 ,4,5 ,6,7,8-

octahydroisoquinoline A solution of 158.0 g. (0.615 mol) of (i)-1-mmethoxybenzyl)l,2,3,4,5,6,7,8-octahydroisoquinoline in 400 ml. of hot ethanol (2B) was added to a refluxing solution of 95.5 g. (0.637 mol) of d-tartaric acid in 950 ml. of ethanol (28). The resulting solution was seeded with a few milligrams of ()-1-m-meth0xybenzyl)- l,2,3,4,5,6,7,8-octahydroisoquinoline d-tartrate and allowed to cool to room temperature with stirring for 15 hours. The crystals were then collected by filtration, washed with ethanol, and dried at 60 over a period of 5 hours under reduced pressure, thus affording 239.0 g. of crude ()-l-(m-methoxybenzyl)-1,2,3,4,5,6,7,8- octahydroisoquinoline d-tartrate, m.p. 170-172. For recrystallization, this compound was dissolved in 2500 ml. of refluxing methanol and then 1900 ml. of the solvent was distilled off at atmospheric pressure. The concentrated solution was seeded as above with the same ()-base d-tartrate and stirred at room temperature for hours. The crude (-)-1-(m-metlioxybenzyl)- l,2,3,4,5,6,7,8-octahydroisoquinoline d-tartrate after separatiaon and drying amounted to 182.0 g., m.p. l76177. A third recrystallization using the same conditions as above afforded 127.0 g. of material, m.p. 186l 88. A fourth and final recrystallization (the same conditions as above) yielded 106.0 g. of pure l-(m-methoxybenzyl)1,2,3,4,5,6,7,8- octahydroisoquinoline dtartrate, m.p. 191 l93.

EXAMPLE 74 Conversion of ()-1-(m-methoxybenzyl)-l.2.3,4,5,6,7,8- octahydroisoquinoline d-tartrate to the free base 511.5 G. (1.25 mol) of ()-1-(m-methoxybenzyl)- l,2,3,4,5,6,7,8-octahydroisoquinoline d-tartrate was suspended in l l. of water and 500 ml. of concentrated ammonium hydroxide was added. The resulting suspension was extracted with a total of 2.1 l. of ether. The ether extracts were dried (MgSO and removal of the solvent gave 315.5 g. (9871) of crude ()-1-(mmethoxybenzyl)-1,2,3,4,5,6,7,8- octahydroisoquinoline. For analysis a sample of this compound was distilled, b.p. 154158/0.3 mm.

EXAMPLE Preparation of l m-methoxybenzyl l ,2.3,4,5 ,6,7,8- octahydroisoquinoline l-tartrate The filtrates obtained in the preparation of ()-base d-tartrate in Example 73 were concentrated to dryness and the residue was treated with 200 ml. of concentrated ammonium hydroxide and 600 ml. of water. The resulting suspension was extracted with ether (3 X 1 l. The combined ether solutions were dried and the solvent was removed under reduced pressure. The crude (+)-1-(m-methoxybenzyl)-1,2,3.4,5,6,7,8- octahydroisoquinoline. 89.0 g. (0.346 mol), in 200 ml. of hot ethanol (28) was combined with a refluxing solution of 53.8 g. (0.354 mol) of l-tartaric acid in 530 ml. of ethanol (28). The resulting solution was seeded with a few milligrams of (+)-1-(m-methoxybenzyl)- l,2,3,4,5,6,7.8-octahydroisoquinoline l-tartrate and stirred at room temperature for 15 hours. The crystals were then collected by filtration, washed with ethanol and dried at 60 over a period of 5 hours under reduced pressure thus affording 129.4 g. of crude (+)-base 1- tartrate, m.p. 184- 186. This compound was recrystallized, as previously described for the ()-base dtartrate in Example 73 from 3 l. of methanol concentrated to l l. Stirring overnight at room temperature and filtering the crystals gave 112.0 g. (9071) of pure (+)-l-m-methoxybenzyl)-l,2,3,4,5,6,7,8- octahydroisoquinoline 1-tartrate,m.p. 189l9l.

EXAMPLE 76 Conversion of (+)-l-(m-methoxybenzyl)-1,2,3,4,5,6,7,8- octahydroisoquinoline l-tartrate to the free base 378.5 g. (0.93 mol) of (+)-1-(m-methoxybenzyl)- l,2,3,4,5,6,7,8-octahydrois0quinoline l-tartrate was suspended in 1 l. of water and 300 ml. of cone. ammonium hydroxide was added. The resulting suspension was extracted with a total of 3 l. of ether. The ether extracts were dried (mgSO and removal of the solvent gave 236.9 g. of crude (+)-l-(m-metho xybenzyl)- 1,2,3,4,5,6,7,8-octahydroisoquinoline. For analysis a sample of this compound was distilled, b.p. 156-160/0.3 mm.

EXAMPLE 77 Formylation of .(+)-l-(m-methoxybenzyl)1,2,3,4,5,6,7,8- octahydroisoquinoline A mixture of 236.5 g. (0.92 mol) of (+)-1-(m- 

1. A COMPOUND OF THE FORMULA
 2. The compound of claim 1 which is (+)-4-hydroxy-N-cyclopropylmethylmorphinan.
 3. The compound of claim 1 which is (-)-4-hydroxy-N-cyclopropylmethylmorphinan.
 5. The compound of claim 4 which is (+)-4-methoxy-N-cyclopropylmethylmorphinan.
 6. The compound of claim 4 which is (-)-4-methoxy-N-cyclopropylmethylmorphinan. 